11beta, 17beta-dihydroxy-17alpha-methylandrostane-3-ones



11anaomYDRoxY-nv.MET YLANnR STANE- 3-0NES TMilton E. Herr, Kalamazoo, Mich assignor to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan 1 .No Drawing. Application December '5, 1955 Serial No. 550,845

Claims. (Cl. 260-39745) This invention pertains to organic compounds .of the iandrostane series and is more parti'cularly'concerned with 4 novel 11,6,17(3-dihydroxy-l7u-methylandrostane-3-ones of the formula wherein R is selected from hydrogen and methyl. The configuration of the S-hydrogen atom can'be a or 5 and both forms are included within the scope of the present -formula. Said compounds are potent anabolic and androgenic agents and are useful in place of prior anabolic and androgenic agents in known anabolic andandrogenic pharmaceutical preparations. The compounds also are anti-pituitary agents and can beemployed in place of .known antiapituitary agents in pharmaceuticalxformulathe parent 1lfl,17,8-dihydroxy-17a-methylandrostane-3- ones.

The 11B,17B-dihydroxy-17a-methylandrostane-3-ones of the present invention can be prepared readily from the corresponding 11,6 hydroxy 17a methyltestosterones (starting compounds are described in U. S. Patent 2,735,854, filed March 11, 1955) by hydrogenation of the 4-double bond. The hydrogenation can be carried out by catalytic methods, preferably with hydrogen and a palladium catalyst, and preferably using a solvent, e. g., i

an alcohol such as ethyl alcohol. The 11fl,l7}3-dihydroxy- 17-a-alkylandrostane-3-ones and 11fi,l7,B-dihydroxy-17aalkyl-l9-norandrostane-3-ones wherein the alkyl radical is preferably a lower-alkyl radical containing from two to eight carbon atoms, inclusive, e. g., ethyl (particularly preferred), propyl, isopropyl, butyl, secondary butyl, amyl, hexyl, heptyl, octyl, etc., are prepared by the same methods and have similar androgenic, anti-pituitary and ana-- bolic activity.

2,842,57l Patented July 8, 1951 The following examples are illustrative of certain pre ferred processes and products and are not to be con strued as limiting the invention.

Example 1.A solution of one gram of llfl-hydroxy 17a-methyltestosterone in 25 milliliters of percen ethyl alcohol is prepared and milligrams of five per cent palladium on charcoal catalyst is added. The mix ture is then shaken with hydrogen under a pressure 0 about 25 pounds per square inch for several minute when one molar equivalent of hydrogen is reacted. Th

hydrogenated mixture is then filtered to remove the cata lyst and the filtrate evaporated to dryness in vacuo. Abou 25 milliliters of dry benzene is then added to the residu and the resulting mixture again evaporated to drynes: thereby removing last traces of water and alcohol. Th residue is then dissolved in twenty milliliters of methylen chloride, the solution diluted with twenty milliliters c benzene, and the solution evaporated until the methylen chloride is removed and the solid product begins to sepz rate. After standing for sixteen hours at room tempera ture, the precipitate is separated by filtration, washed .wit

benzene (the benzene filtrate and washings being pr: served), and dried to provide 0.379 gram of 1118,17B-d hydroxy?17ix-methyI-Swandrostane-3-one melting at 23 to 244 degrees Centigrade. Recrystallization of this prod not from benzene gave a melting point 250 degrees cent grade (Fisher-Johns block), of plus 23 degrees i chloroform.

Analysis.Calcd. for C H O C, 74.94; H, 10.02 Found: C, 74.87; H, 10.21.

The foregoing benzene filtrate and washings are cor centrated to dryness in vacuo providing 0.620 gram c residue. This residue is dissolved in fifty milliliters c acetone and chromatographed on a column containin fifty grams of a mixture containing two parts of (llfl'K maceous earth (Celite) and one part of activated charcoz (Darco 6-60). Eluting with 800 milliliters of aceton provides 0.502 gram of 11/3,17,8-dihydroxy-17a-methy. 5fl-androstane-3-one which, after crystallization from mixture. of methylene chloride and normal hexane (Skellysolve B), melts at 182 to 184 degrees centigrad (Fisher-Johns block) and has of plus 32 degrees i chloroform.

Analysis.Calcd. for C H O Found: C, 75.25; H, 9.89.

T he foregoing chromatographic column is finally elute with 400 milliliters of methylene chloride and the elual evaporated to dryness to provide an additional 0.047 grat of 1 1b,17/3-dihydroxy-17u-methyl-5ot-androstane-3-0ne.

Example 2.In exactly the same manner as shown i Example 1, hydrogenation of 11fi-hydroxy-l7a-methyl-1S nortestosterone with hydrogen and a palladium-charcoz catalyst provides 1113,17B-dihydroxy-l7a-methyl-19-no1 5a-androstane-3-one and 1 1,9,l7 3-dihydroxy-17a-methy 19-nor-5fl-androstane-3-one. Other 11,8,175-dihydrox3 17a-alkyl-5a(and 5;3)-androstane-3-ones and 11,8,17fl-d hydroxy-l7a-alkyl-l9-nor-5a(and 5/3) androstane-3-one wherein the alkyl radical is as defined and illustrate above, are prepared by the same procedure from corn sponding 11 fl-hydroxy 17a alkyltestosterones and 11; hydroxy-l7a-alkyl-19-nortestosterones.

Example 3.-A solution of 11,9,17B-dihydroxy-17 methyl-5u-androstane-3-one in dry pyridine is treated wit acetic anhydride, the molar ratio of steroid to acetic a1 hydride being about one to three, and the resulting mi ture is heated under reflux for about six hours. The mi: ture is then cooled, diluted with water while stirring, an the solid precipitate obtained removed by filtration. Th solid is washed with two percent aqueous hydrochlori acid solution and with water, and then dried under val uum. Recrystallization or chromatographic separatio .lrostane-3-one, 11B,17fl-dihydroxy-17a-methyl 19 nor- 5a-androstane-3-one and 1113,17,8-dihydroxy-l7a-methy1- 19-nor-5fi-androstane-3-one, respectively, as the starting ;teroid in the foregoing procedure. Substituting the appropriate acylating agent, i. e., the appropriate acid, acid anhydride or acid chloride, for the acetic anhydride in the above process provides other 17-acylates of 113,17B-di- 1ydroxy-17a-methyl-5a(and 5 3)-androstane 3 one and 115,175 dihydroxy-17a-rnethyl- 19 nor-5u(and 5fl)-an- :lrostane-3-one including the 17-formate, propionate, trimethylacetate, furoate, a or fl-cyclohexylpropionate, bcnzoate, phenylacetate, a or fi-cyclopentylpropionate, a or 3- phenylpropionate, methylbenzoate, a: or fl-furylacrylate, valerate, methacrylate, and the like.

Example 4.A mixture of 1113,17fl-dihydroxy-l7amethy1-5a-androstane-3-one ii -acetate, a large excess of acetic anhydride to serve as both acylating agent and solvent, and a trace of the strongly acidic catalyst sulfuric acid is heated at a temperature of about one hundred degrees centigrade for twelve hours. The hot solution then is poured over cracked ice and the resulting mixture ;tirred until hydrolysis of the excess acetic anhydride is :omplete. The solid product which precipitates is removed by filtration, washed with water and dried under vacuum. Purified 1lfl,17;3-dihydroxy-17a-methyl-5a-androstane-3-one 11,17-diacetate is obtained by recrystallization or chromatographic separation. 11,3,17fi-dihyiroxy-17a-methy1-5B-androstane-3-one 11,17-diacetate is obtained in exactly the same manner by substituting l1 [3,17fl-dihydroxy-17a-methy1-5fi-androstane 3 one for the above starting steroid. By substituting the appropriate 1 nor-5a(and 5fi)-androstane-3-one are obtained including the ILI'Z-dipropionate, diacetate, di-(trirnethylacetate), difuroate, (ii-(oz or p-cyclohexylpropionate), dibenzoate, di-(phenylacetate), (ii-(oz or:fl-cyclopentylpropionate), di- (0: or fi-phenylpropionate), di-(methylbenzoates), (ii-(0c or fi-furylacrylates), divalerate, di-(methacrylate), ll-acetate 17-formate, 11-(p-cyclopentylpropionate) 17-acetate, and thelike. The foregoing 17-acylates and 11,17-diacylates can also be prepared by hydrogenation, according tothe procedures of Examples 1 and 2, of corresponding 17- acylates and 11,17-diacylates of llfi-hydroxy-lh-methyltestosterone and 1lfi-hydroxy-l7a-methyl-19-nortestosterone. The 17-monoacylates and 11,17-diacylates of other 1118,17fl-dihydroxy 7 17oz alkyl-5a(and 5 fi)-androstane-3-ones and 11 3,17fl-dihydroxy-17a-alkyl-19-nor-5a (and 5p)-androstane-3-ones, wherein the alkyl and acylate radicals are as defined and illustrated above, also are prepared by the the foregoing procedures.

Iclaim:

1. 11fi,17fl-dihydroxy-l7a-methy1androstane 3 one of the formula OH I am .wherein R is selected from the. group consisting of hydrogen and methyl.

2. 1 1,9,17fi-dihydroxy-17a-rnethyl-5a-androstane-3-one. 3 11,8,l7fl-dihydroxy-l7a-methyl-19 nor 5a-andros- .tane-3-one. I

4. 11,8,l7p dihydroxy-17a-methyl-5/3-androstane-3-one. 5. 115,17,8-dihydroxy-17a-rnethyl-19 nor SB-androstane-3-one.

References Cited in-the file of this patent UNITED STATES PATENTS 2,695,907 Murray et a1 Nov. 30, 1954 

1. 11B,17B-DIHYDROXY-17A-METHYLANDROSTANE-3-ONE OF THE FORMULA 